ANTI FUNGAL DRUGS Nov.2010 PHARMA TEAM 428 Be patient !!

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Introductions Fungal infections are called as mycoses, and they are often chronic in nature. All Eukaryotic organisms Heterotrophic – do not have chlorophyll The cell is surrounded by rigid cell wall made up of chitin & complex polysaccharides. Have simple structure Most of them are microscopic Fungal cell membrane contains ergosterol as the main cell membrane sterol, human cell membrane sterol is composed of cholesterol predominantly.

Groups of fungal infection Superficial Mycoses Subcutaneous Mycoses Opportunistic Mycoses Systemic Mycoses Actinomycetous Infections Cutaneous Mycoses

Superficial Mycoses Dermatophytosis The dermatophytes are subgrouped into 3 genera: Trichophyton: Infect skin + hair + nail Microsporum: Infect skin + hair Epidermophyton floccosum in human: infect skin + nail.

Cont’d 2. Candidiasis (commonly normal flora of mouth, skin, intestines and vagina) infection caused by genus candida affecting skin, mucous membrane of mouth or G.I.T or female genital tract

Systemic mycosis causing agents: Candidiasis ,Cryptococcal meningitis , endocarditis, pulmonary Aspergillosis, Rhinocerebral mucormycosis, Blastomycosis, Histoplasmosis, Coccidioidomycosis, Paracoccidioidomycosis and others

Classification of drugs disrupt cell membrane inhibits mitosis Miscllaneous inhibits DNA synthesis

A) Drugs that disrupt fungal cell membrane i) Polyenes Amphotericin-B , Nystatin ii) Azoles depending on the number of nitrogen groups attached to the 5 ring azole: a) Imidazole Ketoconazole Clotrimazole Econazole Miconazole Oxiconazole Sulconazole b) Triazole Itraconazole, Fluconazole, Voriconazole, &Posaconazole iii) Allylamines Terbinafine, naftifine , & butenafine vi) Echinocandins Caspofungin, micafungin, & anidulafungin,

B) Drugs that inhibits mitosis Penicillin derivatives Griseofulvin C) Drugs that inhibits DNA synthesis Flucytosine D) Miscllaneous Haloprogi Tolnaftate Whitefield's ointment Ciclopirox olamine

A) Dermatophyte infections (ring worm (tinea), Tinea barbae, T A) Dermatophyte infections (ring worm (tinea), Tinea barbae, T. capitis, T.cruris , T. pedis and others) Benzoic acid ointment for mild infection. Topical imidazoles (like miconazole, clotrimazole) are preferred now a days Tioconazole for nail infection Griseofulvin orally for extensive scalp or nail tinea infection.

B) Candidaiasis Cutaneous infection: Treat by topical amphotericin B, clotrimazole econazole, miconazole, or nystatin Candidiasis of elementary tract mucosa Amphotericin B, fluconazole, ketoconazole, miconazole or nystatin. Vaginal candidiasis: Clotrimazole, econazole, ketoconazole, miconazole or nystatin

C) Systemically 1-POLYENE ANTIBIOTICS: e.g. amphotericin B

AMPHOTERICIN B It is amphoteric polyene macrolide. (polyene= contains many double bond. Macrolide= contains a large lactone ring of 12 or more atoms) Insoluble in water Poorly absorbed orally, useful for fungal infection of gastrointestinal tract. Notice the multiple double bonds (lipophillic) which aids in attaching to the fungal cell wall

Highly protein bound Penetration through BBB is poor but increases in inflamed meninges. Excreted slowly via kidneys, traces found in urine for months after cessation of drugs. Half life 15 days Remains in the body for weeks after stopping the drug. No dose adjustment in hepatic or renal impairment Course of treatment lasts 6-12 weeks.

Mechanism of action and resistance Resistance occurs because of: 1-↓ the membrane concentration of ergosterol 2-Modify the target molcule  ↓ affinity of the drug

Clinical uses Locally used in corneal ulcers, candidial bladder irrigation, which proved to be nontoxic, and arthritis by local joint injections For systemic infections given as slow I/V infusion. Drug of choice for most systemic infections, except for using it in cryptococcal meningitis due to the diminished penetration of the BBB Empiric therapy for pt. with high risk for systemic fungal infection Course of treatment lasts for 6-12 weeks.

Adverse reactions: Has a low therapeutic index Most serious is renal toxicity which occurs in 80% of patients. It may cause decrease in glomerular filtration, and tubular acidosis, drop in creatinine clearance, and loss of potassium and magnesium, nephrotoxcity may be potentiated by sodium depletion and decreased by saline infusion. Hypokalaemia in 25% of patients, requiring potassium supplementation.

Cont’d Anemia, of the normochromic normocytic type due to the decreased erythropoieting secreted by damaged renal tubules, Thrombocytopenia Impaired hepatic function Anaphylactic shock Anorexia, nausea, vomiting, abdominal, joint and muscle pain, loss of weight, and fever. Aspirin, antihistamines (H1), antiemetics can be used to reduce these adverse effects Febrile reactions can be reduced by hydrocortisone infusion.

Liposomal preparations of amphotericin B. To reduce the toxicity of amphotericin B ,several new formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery system, to assume that they will less bind to mammalian cell. Lipid vehicle act as a reservoir, reducing binding to human cell. In this way it permits a larger doses, even five times more than normal colloidal preparation, they also have better clearance . Clinically they have more efficacy, less nephrotoxicity, and less infusion toxicity. But these are very expensive.

NYSTATIN It has little toxicity It is polyene macrolide, similar in structure to amphotericin B and with the same mechanism of action. Too toxic for systemic use Only used topically Not absorbed from GIT, skin or vagina, therefore administered orally to prevent or treat superficial candidiasis of the mouth, esophagus, or intestinal tract. It has little toxicity For vaginal candidiasis in the form of pessaries used for 2 weeks

Pessaries: small plastic or silicone medical device inserted into the vagina or rectum and held in place by the pelvic floor musculature. In Cutaneous infection it’s available in cream, ointment or powder form and applied 2-3 times a day Can be used in combination with antibacterial agents and corticosteroids

Flucytosine Has useful activity against Candida and Cryptococcus. It is often used in combination with amphotericin B it is fungistatic, effective in combination with itraconazole for treating chromoblastomycosis and with amphotericin B for treating cryptococcosis.

Flucytosine PK: Absorbed rapidly and well from GIT Widely distributed in body and penetrates well into CSF. Minimally bound to plasma protein Peak plasma con. reaches in 1-2 hours. 80% dose is excreted unchanged in urine. t 1/2 3-6 hours in renal failures it may be 200 hours

MOA Flucytosine is converted to the antimetabolite 5-fluorouracil (5-FU) by the fungus, not human. 5-FU is subsequently converted to 5- fluorodeoxyuridine monophosphate (5-FdUMP) which inhibits thymidylate synthetase enzyme and thus DNA synthesis. Resistant mutants may occur. Thus, is not used alone.

Uses: Side effects: Generally used in combination with amphotericin For cryptococcal meningitis in AIDS patients. Used with itraconazole for chromoblastomycosis Side effects: Reversible neutropenia, anemia, thrombocytopenia and occasional bone marrow depression due to the effect of the drug being metabolized by the microflora to the antineoplastic drug 5-fluorouracil. Nausea ,vomiting ,diarrhea, severe enterocolitis Hepatic enzyme elevation in 5% of patients and is reversible.

AZOLES Broad-spectrum of activity. This group of drugs possess antibacterial, antiprotozoal, anthelminthic, and antifungal effects. These are synthetic, fungistatic agents They produce their effect by inhibiting the fungal cytochrome P450 enzyme , spcifically the enzyme lanosine 14 -desmethylase,which is responsible for converting lanosterol to ergosterol, the main sterol in the fungal cell membrane.

classification azoles triazole imidazoles ketoconazole clotrimazole miconazole triazole itraconazole fluconazole voriconazole posaconazole

A. Imidazoles Inhibit the formation of ergosterol They lack selectivity, and also inhibits human gonadal and adrenal steroid synthesis leading to decreased testosterone and cortisol production. they also inhibit cytochrome P450 –dependant hepatic drug –metabolizing enzyme thus leading to the increase in concentration of CYP-450 dependent drugs, check figure the slide below.

contraindicated

KETOCONAZOLE (Imidazoles ): Well absorbed orally and acidic environment favors its dissolution. Only administered orally Bioavailability is decreased with Rifampin, H2 (histamine) blocking drugs, proton pump inhibitors and antacids and is impaired with food. Cola drinks improve its absorption in patients with achlorhydria (absent gastric acid in stomach) Half life increases with dose and it is 7-8 hrs 84 % is bound to plasma proteins. It does not enter CSF.

MOA and pharmacokinetics

Metabolized extensively in liver and inactive products appear in feces. Moderate hepatic dysfunction has no effect on drug concentration = amphotericin B (for the hepatic part). Induction of microsomal enzymes by other drugs reduces its concentration. Contraindicated in pregnancy

Side effects: It inhibits adrenal and gonadal steroids. which leads to menstrual irregularities, loss of libido, impotency and gynecomastia in males. Its efficacy is poor in immunosuppressed patients and in meningitis. Dose dependant nausea, anorexia ,vomiting Liver toxicity is rare but may prove fatal Hair loss Fluid retention and hypertension

triazole 1/ ITRACONAZOLE It is a new drug It lacks endocrine side effects of ketoconazole. It has broad-spectrum activity Administered orally and IV Food and low gastric pH increase its absorption It is well distributed to body tissues including bone, sputum, and adipose tissue. Highly bound to plasma protein Does not penetrate CSF adequately (just like ketaconazole), not used for meningeal infections. Metabolized in the liver extensively It doesn’t affect mammalian steroid synthesis Reduced bioavailability when taken with rifamycins (rifampin, rifabutin, rifapentine)

Side effects: Half life is 30-40 hours Steady state reaches in 4 days, so loading doses are recommended for deep mycosis. Side effects: Nausea, vomiting Increased liver enzymes, hepatotoxicty, and rash which leads to drug discontinuation. Hypertriglyceridemia Hypokalaemia

2/FLUCONAZOLE Completely absorbed from GIT Concentration in plasma is same by oral or IV route. Bioavailability is not altered by food or gastric acidity (high oral bioavailability) It has the least effect on hepatic microsomal enzymes low drug interaction Widest therapeutic index of azoles thus allowing it to be given in massive doses. It easily penetrates CSF and is the drug of choice in and coccidioidal mycosis and the drug of choice for treatment and prophylaxis in Cryptococcal meningitis.

It can be safely administered prophylactically in patients receiving bone marrow transplants. Resistance is not a problem except in patients with HIV Renal excretion 90%,dose is readjusted in compromised renal function t1/2 25-30 hours. Uses: Candidiasis, Cryptococcosis. In AIDS for life-threatening cases Not effective for invasive aspergillosis (voriconazole is used instead)

Side effects Nausea, vomiting, headache, skin rash, abdominal pain, diarrhea, reversible alopecia. Hepatic failure may lead to death rare It is teratogenic like other azoles.

3/Voriconazole A new drug ,with wider spectrum Drug of choice in for invasive aspergillosis Available in IV and oral formulations. High bioavailability when given orally Predominant hepatic metabolism Reversible visual disturbances, photosensitivity dermatitis occuring within 30 minutes of taking the drug. This phenomenon is unique to voriconazole. It is similar to itraconazole but more potent.

4/Posaconazole Newest triazole Available only in liquid formulation Better absorption with fatty meal It has the broadest-spectrum among the azoles It is the only azole with significant activity against zygomycosis and mucormycosis

Echinocandins: Caspofungin It interferes with the synthesis of fungal cell wall by inhibiting synthesis of β (1-3) glucan. Available IV only It is water soluble and highly bound to serum proteins Has half life of 9-11 hours Slowly metabolized by hydrolysis and N-acetylation Dose adjustment in severe hepatic insufficency Eliminated equally by urinary and fecal route

Clinical uses Adverse effects: Particularly useful for aspergillus and candida. Replaced amphoreicin B for Empirical therapy for febrile neutropenia Adverse effects: vomiting, flushing and elevated liver enzymes It is very expensive!!

Mechanism of action of different anti fungal durgs:

Topical Anti fungal Drugs Used For Topical Fungal Infections azole Nystatin and Amphotericin tolnaftate Terbinafine Butenafine Naftifine Ciclopirox olamine

Oral Anti Fungal Drugs Used For Topical Infections Griseofulvin Terbinafine oral azoles

First, topical In superficial fungal infections drugs confined to thestratum corneum are preferred, squamous mucosa, or cornea. Such disease includes dermatophytosis (ring worm), candidiasis tinea and fungal keratitis. Topical administration of antifungal agents is usually not successful in mycoses of the nails and hair and has no place in the treatment of subcutaneous mycoses. The efficacy of topical agents in the superficial mycoses depends not only on the type of lesion and the mechanism of the drug action but also on the viscosity, hydrophobicity and acidity of the formulation. The preferred formulation for cutaneous application usually is a cream or solution.

IMIDAZOLE AND TRIAZOLES FOR TOPICAL INFECTION These are synthetic azoles and used both topically and systemically Selection depends on cost and availability Should be applied twice a day for 2-3 weeks. Vaginal creams, suppositories and tablets for vaginal candidiasis used once a day preferably at bed time.

CLOTRIMAZOLE Absorption less than 0.5 % from intact skin, 3- 10 % from vagina and activity in vagina remains for 3 days. Its efficacy in cutaneous candidiasis is 80- 100% & In vulvovaginal candidiasis is 80%. Stigma, erythma, edema, vesication, pruritus, urticaria mild vaginal burning sensation may occur.

ITRACONAZOLE * fungal infection of the nail Systemic drug for topical infection. Itraconazole is effective for treatment of onychomycosis* after meal for 3 months Should not be given in patients with ventricular dysfunction Routine evaluation of hepatic function is recommended. should not be used concurrently with midazolam, triazolam, quinidine and HMG-CoA reductase inhibitors. * fungal infection of the nail

TOLNAFTATE Effective in most cutaneous mycosis. It is ineffective against Candida. In tinea pedis cure rate is around 80%. Available in 1% cream,gel,powder and topical solution. Applied locally twice a day. Rarely causes irritation or allergic contact sensitization

TERBINAFINE & Naftifine (topical usage) It is synthetic allylamine It is broad spectrum, fungicidal. Available as 1% cream or gel It is a drug of choice for treating dermatophytes especially onychomycosis It is better tolerated, requires shorter duration of therapy It inhibits fungal squalene epoxidase ,decreases synthesis of ergosterol Also accumulation of toxic amounts of squalene causes cell death. It is fungicidal but activity is limited to C.albicans and dermatophytes. Metabolites are excreted in urine Adverse effects: irritation, burning sensation, erythema Avoid contact with mucous membrane.

TERBINAFINE (systemic usage) Quite effective for the treatment of onychomycosis for 6 weeks for finger nail infection and for 12 weeks in toe nail infection Well absorbed orally, bioavailability decreases due to first pass metabolism in liver. Protein binding more than 99% in plasma. Drug accumulates in skin, nails and fat. severely hepatotoxic , liver failure even death.

Initial half life 12 hrs but extends to 200-400 hrs ,which reflects it slow release from the tissues Can be found in plasma for 4- 8 weeks after prolong therapy. Clearance is reduced in moderate and hepatic impairment. Not recommended in azotemia or hepatic failure. Dose 250 mg for 3 months/for local infection applied twice daily. Side effects GIT disturbance ,Taste and visual disturbance ,transient rise in serum liver enzymes. Rifampicin decreases its blood levels and cimetidine increases it.

GRISEOFULVIN It has been largely replaced by terbinafine for treatment of dermatophytosis of the nails. Insoluble It is fungistatic for species of dermatophytes. it has narrow spectrum as opposed to terbinafine which is fungicidal. It interacts with microtubules and interferes with mitosis.

Inhibition of mitosis by Griseofulvin

PK Absorption increases with fatty meal It is ineffective topically. Barbiturates decreases the absorption from GIT. Extensively metabolized in liver. Drug is deposited in keratin, nail, and hair are 1st to get rid of disease.

Induction of P-450 cytochromes

Not effective in subcutaneous or deep mycoses. Uses: Mycotic diseases of the skin, hair (particularly of the scalp), nail It is also highly effective in athlete's foot Treatment required is 1 month for scalp and hair ringworm, 6-9 months for finger nails, and at least 1 year for toe nails. Not effective in subcutaneous or deep mycoses.

Adverse effects: Headache Peripheral neuritis , lethargy , mental confusion, impairment in performance of routine task, fatigue, vertigo ,syncope, blurred vision. Hepatitis Serum sickness syndrome Leukopenia and proteinuria Interacts with warfarin and phenobarbital Cross-reactivity with penicillin Contraindicated in: porphyria, hepatic failure, and in case of hypersensitivity reactions.

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